In many diseases, compensatory changes occur in tissue cells with the progress of pathology to achieve a temporary equilibrium. In the process of further aggravation of pathology, the compensatory mechanism breaks down leading to cellular dysfunction and finally cellular death. This cellular dropout makes it more difficult to cure diseases and invites unfavorable prognosis or recurrence. Especially in the therapy of diseases in non-regenerative organs such as heart, brain and kidney, it is important to suppress cellular necrosis/dropout.
(1) Heart Diseases
a. Heart Failure: Heart failure is defined as a condition in which the heart cannot maintain an adequate cardiac output to various organs due to reduced myocardial contractility. As a preliminary stage to heart failure, compensatory remodeling occurs in the heart for the purpose of maintaining normal systemic circulation. At this stage, cardiac myocytes continuously enlarge and grow to maintain a high cardiac pumping pressure as well as cardiac output; but at the same time fibrosing in cardiac tissue advances to increase a load imposed on contracted cells. When the balance between the load on cardiac myocytes and compensation by enlargement reaches a limit, heart function breaks down leading to heart failure. It is known that contractility is lowered in cardiac myocytes under heart failure condition (Am J Physiol 1997 Vol. 273(1 Pt 2), H183-91). Conventional therapies for chronic heart failure involve administering cardiac stimulants that increase myocardial contractility such as digitalis and xanthine drugs after a patient falls into heart failure condition or fails to be able to lead a normal daily life. However, these drugs have been shown to promote cellular death, and to cause a deterioration in survival rates due to overconsumption of myocardial energy during prolonged administration. Recently, therapies with β-blockers and ACE inhibitors have been prevailing that reduce overload on the heart by the inhibition of the sympathetic nervous system and the inhibition of the renin-angiotensin system, respectively, that are activated at the compensatory remodeling stage. However, these drugs are less effective for patients who already have a heart failure condition, but rather act prophylactically against chronic heart failure because they have an action of mechanism based on preventing enlargement of cardiac myocytes. Moreover, the fact that long-term survival rates of patients with chronic heart failure have not fully improved even after these drugs came to the market suggests a limit to the action of mechanism of these drugs. Therefore, there is an urgent need for development of a novel therapeutic agent for chronic heart failure that is able to improve both quality of life and survival rates at the chronic heart failure stage after breakdown at the compensatory stage. It would be desirable to develop a novel drug for treating cellular death and cellular dysfunction, which are essential causes of the breakdown mechanism associated with the transition from the compensatory stage to the failure stage.
b. Ischemic Heart Diseases: Ischemic heart diseases are characterized by coronary flow failure including angina pectoris and myocardial infarction. For example, angina pectoris is classified into angina pectoris decubitus and angina pectoris of effort. Currently, serious cases are surgically treated to physically dilate vessels and then place a stent or the like. Relatively mild cases are treated with vasodepressors for treating an attack such as nitrates, nitroglycerin and nicorandil. Cholesterol reducers and anticoagulant agents are formulated for the purpose of preventing infarction. Thus, therapies for acute stage or improving blood circulation are being established. Attack is thought to result from the lowered myocardial adaptability due to the accumulation of injuries caused by chronic ischemia at the subclinical stage. However, no therapy has been established for this phase at present. It would also be desirable to prevent massive ischemia from the onset of angina because many cases show transition from angina to severe myocardial infarction, but a therapy suitable for this phase has not been found yet, either.
(2) Neurodegenerative Diseases
Neurodegenerative diseases are characterized by neuronal degeneration, and specifically include injuries of the white matter such as cerebral infarction, Alzheimer's disease, Parkinson's disease, brain trauma, Huntington's chorea, cerebrovascular dementia, motor neuron degeneration and Binswanger's disease. An excessive increase of the extracellular level of a neurotransmitter glutamate has been commonly found in cerebral infarction, cerebrovascular dementia, brain trauma, Alzheimer's disease, motor neuron degeneration, Parkinson's disease, etc. (Eur J Neurosci 2000 Vol. 12(8), 2735-45; Brain Res 1994 Vol. 11, No. 642(1-2), 117-122; Acta Neurochir Suppl. 2000 Vol. 76, 437-8; Neurosci Lett 2001 Vol. 299(1-2), 37-40; J Neurosci Res 2001 Vol. 63(5), 377-87; Drugs Aging 2001 Vol. 18(10), 717-24). This excessive glutamate stimulates glutamate receptors (NMDA receptors) on the surfaces of neurons to induce excessive neural excitation. It is widely accepted that this excessive neural excitation induces breakdown of intracellular ionic environments to cause cellular death. Currently used therapeutic agents for cerebral infarction such as antiplatelet drugs and thrombolytic agents are intended to reopen and maintain blood flow, but any therapy having a protective effect on neurons themselves has not been established. NMDA receptor antagonists, glutamate release inhibitors and active oxygen scavengers are being developed as therapeutic agents at a testing stage, but have not been verified for their efficacy. Choline esterase inhibitors were recently approved as therapeutic agents for Alzheimer's disease, but they have a mechanism based on improving learning function by promoting intercellular signal transduction rather than directly suppressing neuronal death. It would be desirable to develop a therapeutic agent having an action mechanism based on neuronal protection as an effective therapy for a series of neurodegenerative diseases.
(3) Rheumatism
Among rheumatic diseases, rheumatoid arthritis is chronic arthritis characterized by continuous proliferation of articular synovial membranes and said to be caused by autoimmunization. It is thought that aging and hereditary predisposition are combined with environmental factors to form complex risk factors inducing immunization against autoantigens after some articular inflammation such as infectious diseases. In advanced rheumatoid arthritis, not only cartilage destruction and bone destruction but also chondroblast death and osteoblast death have been reported (Arthritis Rheum 1999 Vol. 42(7), 1528-37; Z Rheumatol 2000 Vol. 59, Suppl. 1, 10-20). The disease seems to enter into an irreversible stage upon chondroblast and osteoblast death. Current therapies are based on immunosuppression using steroid or non-steroid drugs, but their therapeutic effects are neither sustained nor radical. Thus, it would be desirable to develop a novel therapeutic agent having a mechanism based on the protection of joints, osteoblasts and chondroblasts.
(4) Renal Diseases
Among renal diseases, chronic renal failure is characterized by injury to glomeruli and renal tubules in the kidney, and specifically includes diabetic nephropathy, hypertensive nephropathy, lupus nephropathy, etc. Abnormal functions in glomeruli serving to filter waste products in blood, and in renal tubules serving to reabsorb filtrate from urine, result from cellular injury caused by glycoproteins derived from hyperglycemia, cellular injury by hypertensive circulation failure and autoimmune chronic nephritis. An effective therapy for chronic renal failure has not been found at present, and symptomatic therapies are applied such as steroid or non-steroid drugs for inflammation such as lupus nephritis and antihypertensives for hypertensive renal failure. It would be desirable at present to provide a drug directly acting on glomerular cells and tubular cells to protect them.
(5) Hepatic Diseases
Hepatic diseases progress to cirrhosis and hepatic failure via viral, alcoholic and drug-induced hepatitis. Symptomatic therapies therefor include ursodeoxycholic acid, glycyrrhizin drugs and herbal medicine. Interferon therapy is a causal therapy for viral hepatitis, but has strong side effects and insufficient therapeutic effect. It can be said that hepatic failure such as cirrhosis is caused by chronic overstress on the liver, which is originally a regenerative organ but fails to regenerate hepatic function. Thus, protection of hepatic cells may be clearly effective for preventing hepatic failure. However, an effective therapy with few side effects has not been found at present.
On the other hand, AOP-1 gene was identified as a factor whose expression level increases when mouse erythroleukemia cells are induced by DMSO to differentiate (Gene 1989 Vol. 80, 337-343: initially named MER-5, and later AOP-1). Subsequently, AOP-1 protein was found to belong to the peroxiredoxin family and became to be commonly called peroxiredoxin 3 (PRx3) in the literature (AOP-1 protein is hereinafter referred to as AOP-1). The peroxiredoxin family is a class of proteins characterized by thiol-specific antioxidant activity by biochemical analysis using purified proteins (Proc. Natl. Acad. Sci. USA 1994 Vol. 91, 7017-7021) and widely conserved from prokaryotes to higher organisms including human. Recently, analysis using bacterial peroxiredoxin showed that peroxiredoxins are capable of scavenging peroxynitrite (Nature 2000 vol. 407, No. 14, 211). In the peroxiredoxin family, AOP-1 is distinguished from other peroxiredoxins in that it is localized in mitochondria (Methods in enzymology, vol. 300). Superoxide dismutase (SOD) and catalase that are widely known as antioxidant proteins do not demand the thiol group for producing antioxidant activity and they cannot scavenge peroxynitrite, so that the peroxiredoxin family is also expected to differ in physiological functions from SOD and catalase. Recently, protective effect against hydrogen peroxide injury in cultured thyroid cells was found as a physiological function of peroxiredoxin type 1 and type 2 localized in the cytoplasm (J. Biological Chemistry 2000 Vol. 275, No. 24, 18266-18270), but a physiological function of AOP-1 (peroxiredoxin type 3) localized in mitochondria has not been found. The direct relation of the peroxiredoxin family including AOP-1 to any disease has not been shown, either.
The present invention aims to provide a method for preventing, treating or diagnosing diseases associated with decreased expression of AOP-1 gene or AOP-1 such as heart diseases (chronic heart failure, ischemic heart failure, ischemic heart diseases, etc.), neurodegenerative diseases (cerebral infarction, Alzheimer's disease, Parkinson's disease, brain trauma, Huntington's chorea, cerebrovascular dementia, motor neuron degeneration, Binswanger's disease, etc.), rheumatism (rheumatoid arthritis, etc.), renal diseases (renal failure, etc.), hepatic diseases (hepatitis, cirrhosis, hepatic failure, etc.), a prophylactic or therapeutic drug for these diseases, a method for screening a material suitable as an active ingredient of said drug, a non-human transgenic animal and transformed tissue in which the expression of AOP-1 gene is suppressed or deleted, etc.